Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis

doi:10.1016/S0140-6736(14)61704-9

The Lancet

Volume 386, Issue 9990, 18–24 July 2015, Pages 258-265

https://doi.org/10.1016/S0140-6736(14)61704-9 Get rights and content

Summary

Background

Serious infections are a major concern for patients considering treatments for rheumatoid arthritis. Evidence is inconsistent as to whether biological drugs are associated with an increased risk of serious infection compared with traditional disease-modifying antirheumatic drugs (DMARDs). We did a systematic review and meta-analysis of serious infections in patients treated with biological drugs compared with those treated with traditional DMARDs.

Methods

We did a systematic literature search with Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to Feb 11, 2014. Search terms included “biologics”, “rheumatoid arthritis” and their synonyms. Trials were eligible for inclusion if they included any of the approved biological drugs and reported serious infections. We assessed the risk of bias with the Cochrane Risk of Bias Tool. We did a Bayesian network meta-analysis of published trials using a binomial likelihood model to assess the risk of serious infections in patients with rheumatoid arthritis who were treated with biological drugs, compared with those treated with traditional DMARDs. The odds ratio (OR) of serious infection was the primary measure of treatment effect and calculated 95% credible intervals using Markov Chain Monte Carlo methods.

Findings

The systematic review identified 106 trials that reported serious infections and included patients with rheumatoid arthritis who received biological drugs. Compared with traditional DMARDs, standard-dose biological drugs (OR 1·31, 95% credible interval [CrI] 1·09–1·58) and high-dose biological drugs (1·90, 1·50–2·39) were associated with an increased risk of serious infections, although low-dose biological drugs (0·93, 0·65–1·33) were not. The risk was lower in patients who were methotrexate naive compared with traditional DMARD-experienced or anti-tumour necrosis factor biological drug-experienced patients. The absolute increase in the number of serious infections per 1000 patients treated each year ranged from six for standard-dose biological drugs to 55 for combination biological therapy, compared with traditional DMARDs.

Interpretation

Standard-dose and high-dose biological drugs (with or without traditional DMARDs) are associated with an increase in serious infections in rheumatoid arthritis compared with traditional DMARDs, although low-dose biological drugs are not. Clinicians should discuss the balance between benefit and harm with the individual patient before starting biological treatment for rheumatoid arthritis.

Funding

Rheumatology Division at the University of Alabama at Birmingham.

Introduction

Biological drugs are a new class of disease-modifying treatment options for rheumatoid arthritis that have been reported to show large clinical and radiographic improvements compared with traditional drugs.1, 2 Nine biological drugs are now approved by the US Food and Drug Administration and European Medicines Agency for treatment of rheumatoid arthritis. Biological drugs are used to treat moderate-to-severe rheumatoid arthritis in patients who have not responded adequately to traditional disease-modifying antirheumatic drugs (DMARDs), such as methotrexate.3, 4 Infections, especially serious infections, are one of the greatest concerns for patients considering treatment with biological drugs.

Debate continues on whether biological therapies are associated with serious infections in patients with rheumatoid arthritis, the magnitude of this risk, and whether the risk varies between subpopulations of patients with rheumatoid arthritis.⁵ In our experience, the clinical perception tends towards a belief that serious infection is an issue, but this notion is not backed up by consistent research evidence. The confusion originates from the four published systematic reviews with meta-analyses6, 7, 8, 9 of the risk of serious infection in patients receiving biological drugs for rheumatoid arthritis. The first meta-analysis,⁹ which included three of the approved biological drugs in nine trials, reported an association. However, the next three meta-analyses,6, 7, 8 which included more biological drugs and far greater sample sizes, did not identify any association between standard-dose biological drugs and increased risk of serious infections. Furthermore, discordant results have also been reported for non-randomised studies that assessed the risk of serious infection in rheumatoid arthritis,10, 11, 12, 13, 14, 15, 16 with some studies14, 15, 16 detecting an association and others10, 11, 12, 13 detecting no association. Accordingly, the risk of serious infection in biological treatment of patients with rheumatoid arthritis has been debated. Unlike previous analyses, many more trials are now available for a conclusive study to address this question. Additionally, all four meta-analyses6, 7, 8, 9 in patients with rheumatoid arthritis6, 7, 8, 9 had major limitations; they restricted the population of patients (eg, only methotrexate-naive patients),⁸ only included a few biological drugs in their analyses,6, 7, 8, 9 consisted mainly of studies that were more than a decade old,⁹ or did not integrate findings across low-dose, standard-dose, or high-dose biological drugs (ie, did analyses separately). Availability of more robust evidence is crucial for the development of guidelines for rheumatoid arthritis treatment, which have previously been based mainly on observational studies.³

We aimed to compare the risk of serious infections in rheumatoid arthritis between biological treatment and non-biological traditional treatment with DMARDs, and use network meta-analysis to compare subpopulations within rheumatoid arthritis, to synthesise data from randomised trials.

Section snippets

Search strategy and selection criteria

We did a systematic review that included both a traditional meta-analysis and network meta-analysis to assess the risk of serious infection in rheumatoid arthritis, comparing biological drugs with each other, placebo, or a control treatment (traditional DMARDs or their combinations). Network meta-analysis includes direct and indirect evidence of benefits and harm among multiple treatments simultaneously, whereas traditional meta-analysis only considers direct evidence between two treatment

Results

We identified 106 randomised trials published between 1992 and Feb 11, 2014, which included 42 330 patients with rheumatoid arthritis (figure 1; appendix pp 10–21). We separated these studies into those that included methotrexate-naive, traditional DMARD-experienced, and anti-TNF biological drug-experienced patients (table; figure 2). Treatment duration ranged from 2 to 36 months, and the mean rheumatoid arthritis duration ranged from 0·1 to 13·5 years (table). Randomised trials reported

Discussion

The risk of serious infection for patients receiving biological treatment for rheumatoid arthritis and the magnitude of this effect are uncertain. Although the first meta-analysis of the association between biological drugs and serious infections detected an association, three subsequent meta-analyses reported that standard-dose biological drugs were not associated with an increased risk of serious infection compared with traditional DMARDs. Evidence can now be drawn from data for 42 330

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ArticlesRisk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Search strategy and selection criteria

Results

Discussion

Lancet

Value Health

Value Health

Biologicals for rheumatoid arthritis

BMJ

2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis

Arthritis Care Res (Hoboken)

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update

Ann Rheum Dis

Biologic agents in rheumatology: unmet issues after 200 trials and $200 billion sales

Nat Rev Rheumatol

The safety of anti-tumour necrosis factor treatments in rheumatoid arthritis: meta and exposure-adjusted pooled analyses of serious adverse events

Ann Rheum Dis

Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of randomised placebo-controlled trials

Ann Rheum Dis

Tumor necrosis factor therapy and the risk of serious infection and malignancy in patients with early rheumatoid arthritis: a meta-analysis of randomized controlled trials

Arthritis Rheum

Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials

JAMA

Serious infection following anti-tumor necrosis factor alpha therapy in patients with rheumatoid arthritis: lessons from interpreting data from observational studies

Arthritis Rheum

Anti-tumor necrosis factor alpha therapy and the risk of serious bacterial infections in elderly patients with rheumatoid arthritis

Arthritis Rheum

Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy

Arthritis Rheum

Initiation of tumor necrosis factor-alpha antagonists and the risk of hospitalization for infection in patients with autoimmune diseases

JAMA

Time-dependent increase in risk of hospitalisation with infection among Swedish RA patients treated with TNF antagonists

Ann Rheum Dis

Articles
Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis